anticancer Flashcards
what are the 2 mechanisms of chemotherapy resistnace
- Primary resistance, which refers to the tumour being insensitive to the drug from its first exposure, and this can be due to the intrinsic genetic property of the individual tumour cell.
- Acquired resistance, which develops over time, after the initial exposure to the drug, and there are a few mechanisms that mediate this resistance:
what are the 5 mechanisms of acquired resistance
- Increased DNA repair.
- Changes in the target enzyme.
- Drug inactivation
- Decreased drug accumulation - in multi drug resistance (MDR), there is resistance to drugs of differing structures following exposure to a single agent.
Potentially might be because of the over expression of P-glycoprotein, an efflux transporter which pumps the drug out of the cell, and decreasing intracellular concentrations of the drug, reducing its efficacy. - Alternative metabolic pathways.
what are the 2 main classes of antitumour therapy
- cell cycle specific
- non cell cycle specific
what are the different classes of cell cycle speicfic antitumour drugs
folate metabolism - methotrexate
purine metabolism - 6-mercaptopurine (from prodrug azithiopurine)
pyramidine metabolism - 5-FU
nucleotide incorporation - cytarabine or thioguanine
what are the difference classes of non cell cycle specific drugs
direct DNA modifications
1a. alkylating agents - carmustin, cyclophosphamide
1b. bleomycins
1c. platinum agents - cisplatin, carboplatin
topoisomerase inhibitors
2a. antitumor antibody - doxorubicin
2b. epipodophyllotoxins - etoposide
microtubule inhibitors
3a. vinca alkaloids - vincristine, vinblastin
3b. taxanes - paclitaxel
what does methotrexate do
- reversibly inhibits DHFR (converts DHF into THF –> decreased synthesis of thymidine and purine, required in DNA and RNA synthesis
- induces apoptosis
S phase specificwhat
what does 6-MP do
from azathiopurine (prodrug) to 6-MP, then to T-IMP (hypoxanthine guanine phosphoribosyl transferase HGPRT catalyses this) T-IMP has 3 actions:
1. Feedback inhibition of the already committed first step of purine synthesis
2. inhibits IMP dehydrogenase, which converts IMP into AMP/GMP required for DNA synthesis
3. T-IMP converted into T-GMP, then di/tri phosphorylated, integrated into RNA and then converted to be incorporated into DNA., results in the formation of a non-functional DNA.
regulated by allopurinal
6-MP broken down by xanthine oxidase (allo inhibits), hence allo increases MP toxicity
what does 5-FU do
5-FU converted inot F-dUMP with the same pathway that converted uracil into dUMP. F-dUMP inhibits the thymidylate synthase, which converts dUMP into dTMP (thymidine) for it to be integrated into the DNA. ‘thymidineless death” - imbalanced cell growth, die
5-FU can also be incorportted into DNA, then cleaved out by glycosylase, and this damages the DNA
nucleotide incorporation ddrugs got 2, one is guanine analogue, one is cytadine analoge
explain them
guanine analog is thioguanine, and is converted into 6-thioGMP by HGPRT, then into 6-thioGTP by guanylyl synthase. then has effects similar to the 6-mp/t-imp
1. incorporated into DNA
2. inhibits IMP dehydrogenase, decreasing levels of AMP//GMP
cytidine analogue is the cytarabine, which is metabolised into araCTP, and then it competes with CTP to bind to DNA polymerase, effectively inhbiting hte DNA pol. can be incorporated into the DNA sequence, leading to its termination
what does cyclophosphamide / carmustin do
alkylating agents,
adds an alkyl group to the N-side of guanine in one of both strands of the DNA
- preventing DNA separation (cannot replicate, cannot transcribe)
- alkylates proteins nad eynzymes
- strand breakages
does not discriminate (resting, cycling cells) but higher affinity for the cycling ones, every cell in the body
dna damge more than repair, die
what are the diff dose limiting toxities (got 4)
plats / cisplatin - nephrotoxicity
bleomycin - pulmonary fibrosis
doxorubicin - cardiotoxicity
taxanes / paclitaxel - neutropenia. leukopenia, peripheral neuropathy
other side effects
methtrexate (DHFR inhibitor) - bone marrow (immunosuppression), GIT (gastric acid secretion)
etoposide (epipodophyllotoxins) - bone marrow suppression
vinca alkaloids -
vincristine - peripheral neuropathy
vinblastine - myelosuppression
what does bleomycin do?
binds to DNA, frming a DNA-bleomnycin-Fe2+ complex, then gets oxidsed into Fe3+-bleomycin and liberates an electron, which reacts with O2 to form free radicals, attachs the phosphodiester bond, causing single and double strand DNA breakage.
dose limiting toxicity - cardiotoxicity
what does platinums do (cisplatin, carboplatin)
targeting the nucleophilic site of DNA guanine, cytosine, adenine, causing cross linkages of adjacent DNA residues on the same strand
dose limiting toxicity is nephrotoxicity
what does doxorubicin do
its an antitumour antibiotic, intercalated into the DNA, but prevents the relegation of the DNA strand, resultin g
got a hydroquinone moiety that allows the compound to accept/donate electrons to generate free radicals. Therefore the strand is broken causing cell death.
dose limiting toxicity is cardiotoxicity
what does epipodophyllotoxins like etoposide do
inhibits topoisomerase II mediated relegation, resulting in strand breakages and DNA damage
